Most of the time, we learn only gradually, incrementally building connections between actions or events and outcomes. But there are exceptions—every once in a while, something happens and we immediately learn to associate that stimulus with a result. For example, maybe you have had bad service at a store once and sworn that you will never shop there again.

This type of one-shot learning is more than handy when it comes to survival—think, of an animal quickly learning to avoid a type of poisonous berry. In that case, jumping to the conclusion that the fruit was to blame for a bout of illness might help the animal steer clear of the same danger in the future. On the other hand, quickly drawing connections despite a lack of evidence can also lead to misattributions and superstitions; for example, you might blame a new food you tried for an illness when in fact it was harmless, or you might begin to believe that if you do not eat your usual meal, you will get sick.

Scientists have long suspected that one-shot learning involves a different brain system than gradual learning, but could not explain what triggers this rapid learning or how the brain decides which mode to use at any one time.

Now Caltech scientists have discovered that uncertainty in terms of the causal relationship—whether an outcome is actually caused by a particular stimulus—is the main factor in determining whether or not rapid learning occurs. They say that the more uncertainty there is about the causal relationship, the more likely it is that one-shot learning will take place. When that uncertainty is high, they suggest, you need to be more focused in order to learn the relationship between stimulus and outcome.

The researchers have also identified a part of the prefrontal cortex—the large brain area located immediately behind the forehead that is associated with complex cognitive activities—that appears to evaluate such causal uncertainty and then activate one-shot learning when needed.

The findings, described in the April 28 issue of the journal PLOS Biology, could lead to new approaches for helping people learn more efficiently. The work also suggests that an inability to properly attribute cause and effect might lie at the heart of some psychiatric disorders that involve delusional thinking, such as schizophrenia.

"Many have assumed that the novelty of a stimulus would be the main factor driving one-shot learning, but our computational model showed that causal uncertainty was more important," says Sang Wan Lee, a postdoctoral scholar in neuroscience at Caltech and lead author of the new paper. "If you are uncertain, or lack evidence, about whether a particular outcome was caused by a preceding event, you are more likely to quickly associate them together."

The researchers used a simple behavioral task paired with brain imaging to determine where in the brain this causal processing takes place. Based on the results, it appears that the ventrolateral prefrontal cortex (VLPFC) is involved in the processing and then couples with the hippocampus to switch on one-shot learning, as needed.

Indeed, a switch is an appropriate metaphor, says Shinsuke Shimojo, Caltech's Gertrude Baltimore Professor of Experimental Psychology. Since the hippocampus is known to be involved in so-called episodic memory, in which the brain quickly links a particular context with an event, the researchers hypothesized that this brain region might play a role in one-shot learning. But they were surprised to find that the coupling between the VLPFC and the hippocampus was either all or nothing. "Like a light switch, one-shot learning is either on, or it's off," says Shimojo.

In the behavioral study, 47 participants completed a simple causal-inference task; 20 of those participants completed the study in the Caltech Brain Imaging Center, where their brains were monitored using functional Magnetic Resonance Imaging. The task consisted of multiple trials. During each trial, participants were shown a series of five images one at a time on a computer screen. Over the course of the task, some images appeared multiple times, while others appeared only once or twice. After every fifth image, either a positive or negative monetary outcome was displayed. Following a number of trials, participants were asked to rate how strongly they thought each image and outcome were linked. As the task proceeded, participants gradually learned to associate some of the images with particular outcomes. One-shot learning was apparent in cases where participants made an association between an image and an outcome after a single pairing.

The researchers hypothesize that the VLPFC acts as a controller mediating the one-shot learning process. They caution, however, that they have not yet proven that the brain region actually controls the process in that way. To prove that, they will need to conduct additional studies that will involve modifying the VLPFC's activity with brain stimulation and seeing how that directly affects behavior.

Still, the researchers are intrigued by the fact that the VLPFC is very close to another part of the ventrolateral prefrontal cortex that they previously found to be involved in helping the brain to switch between two other forms of learning—habitual and goal-directed learning, which involve routine behavior and more carefully considered actions, respectively. "Now we might cautiously speculate that a significant general function of the ventrolateral prefrontal cortex is to act as a leader, telling other parts of the brain involved in different types of behavioral functions when they should get involved and when they should not get involved in controlling our behavior," says coauthor John O'Doherty, professor of psychology and director of the Caltech Brain Imaging Center.

Researchers at Caltech have discovered how an abundant class of RNA genes, called long non-coding RNAs (lncRNAs, pronounced link RNAs) can regulate key genes. By studying an important lncRNA, called Xist, the scientists identified how this RNA gathers a group of proteins and ultimately prevents women from having an extra functional X-chromosome—a condition in female embryos that leads to death in early development. These findings mark the first time that researchers have uncovered the detailed mechanism of action for lncRNA genes.

"For years, we thought about genes as just DNA sequences that encode proteins, but those genes only make up about 1 percent of the genome. Mammalian genomes also encode many thousands of lncRNAs," says Assistant Professor of Biology Mitch Guttman, who led the study published online in the April 27 issue of the journal Nature. These lncRNAs such as Xist play a structural role, acting to scaffold—or bring together and organize—the key proteins involved in cellular and molecular processes, such as gene expression and stem cell differentiation.

Guttman, who helped to discover an entire class of lncRNAs as a graduate student at MIT in 2009, says that although most of these genes encoded in our genomes have only recently been appreciated, there are several specific examples of lncRNA genes that have been known for decades. One well-studied example is Xist, which is important for a process called X chromosome inactivation.

All females are born with two X chromosomes in every cell, one inherited from their mother and one from their father. In contrast, males only contain one X chromosome (along with a Y chromosome). However, like males, females only need one copy of each X-chromosome gene—having two copies is an abnormality that will lead to death early during development. The genome skirts these problems by essentially "turning off" one X chromosome in every cell.

Previous research showed that Xist is essential to this process and does this by somehow preventing transcription, the initial step of the expression of genes on the X chromosome. However, because Xist is not a traditional protein-coding gene, until now researchers have had trouble figuring out exactly how Xist stops transcription and shuts down an entire chromosome.

"To start to make sense of what makes lncRNAs special and how they can control all of these different cellular processes, we need to be able to understand the mechanism of how any lncRNA gene can work. Because Xist is such an important molecule and because so much is known about what it does, it seemed like a great system to try to dissect the mechanisms of how it and other lncRNAs work," Guttman says.

lncRNAs are known to corral and organize the proteins that are necessary for cellular processes, so Guttman and his colleagues began their study of the function of Xist by first developing a technique to find out what proteins it naturally interacts with in the cell. With a new method, called RNA antisense purification with mass spectrometry (RAP-MS), the researchers extracted and purified Xist lncRNA molecules, as well as the proteins that directly interact with Xist, from mouse embryonic stem cells. Then, collaborators at the Proteome Exploration Laboratory at Caltech applied a technique called quantitative mass spectrometry to identify those interacting proteins.

"RNA usually only obeys one rule: binding to proteins. RAP-MS is like a molecular microscope into identifying RNA-protein interactions," says John Rinn, associate professor of stem cell and regenerative biology at Harvard University, who was not involved in the study. "RAP-MS will provide critically needed insights into how lncRNAs function to organize proteins and in turn regulate gene expression."

Applying this to Xist uncovered 10 specific proteins that interact with Xist. Of these, three—SAF-A (Scaffold attachment factor-A), LBR (Lamin B Receptor), and SHARP (SMRT and HDAC associated repressor protein)—are essential for X chromosome inactivation. "Before this experiment," Guttman says, "no one knew a single protein that was required by Xist for silencing transcription on the X chromosome, but with this method we immediately found three that are essential. If you lose any one of them, Xist doesn't work—it will not silence the X chromosome during development."

The new findings provide the first detailed picture of how lncRNAs work within a cellular process. Through further analysis, the researchers found that these three proteins performed three distinct, but essential, roles. SAF-A helps to tether Xist and all of its hitchhiking proteins to the DNA of the X chromosome, at which point LBR remodels the chromosome so that it is less likely to be expressed. The actual "silencing," Guttman and his colleagues discovered, is done by the third protein of the trio: SHARP.

To produce functional proteins from the DNA (genes) of a chromosome, the genes must first be transcribed into RNA by an enzyme called RNA polymerase II. Guttman and his team found that SHARP leads to the exclusion of polymerase from the DNA, thus preventing transcription and gene expression.

This information soon may have clinical applications. The Xist lncRNA silences the X chromosome simply because it is located on the X chromosome. However, previous studies have demonstrated that this RNA and its silencing machinery can be used to inactivate other chromosomes—for example, the third copy of chromosome 21 that is present in individuals with Downs' syndrome.

"We are starting to pick apart how lncRNAs work. We now know, for example, how Xist localizes to sites on X, how it silences transcription, and how it can change DNA structure," Guttman says. "One of the things that is really exciting for me is that we can potentially leverage the principles used by lncRNAs, move them around in the genome, and use them as therapeutic agents to target specific defective pathways in disease."

"But I think the real reason why this is so important for our field and even beyond is because this is a different type of regulation than we've seen before in the cell—it is a vast world that we previously knew nothing about," he adds.

The study was supported by funding from the Gordon and Betty Moore Foundation, the Beckman Institute, the National Institutes of Health, the Rose Hills Foundation, the Edward Mallinckrodt Foundation, the Sontag Foundation, and the Searle Scholars Program.

Caltech seniors Janani Mandayam Comar and Aaron Krupp have been named 2015 Thomas J. Watson Fellowship winners. Each fellowship is a grant of $30,000 awarded to seniors graduating from a selected group of colleges. According to the Watson Foundation's website, "Fellows conceive original projects, execute them outside of the United States for one year and embrace the ensuing journey. They decide where to go, who to meet and when to change course." Fifty fellows were selected from a pool of nearly 700 candidates.

Janani Mandayam Comar is a biology major from Downers Grove, Illinois. During her Watson year abroad, she will be using Bharatanatyam, a classic dance form from the Indian state of Tamil Nadu, to reflect the experiences of various "outsider" communities. "Bharatanatyam was originally an exclusively female way of connecting with God," Comar says. "It was revived in the early 1900s as a way to tell stories through movement, and it is now danced by both men and women, and is no longer confined to Indian communities."

In Australia, Comar will be working with the transgender community, whose situation is in some ways mirrored by traditional Indian culture. "Hindu mythology has a lot of transgender elements although the subject is taboo in modern Indian society," she explains. In South Africa, home of the oldest expatriate Indian community in the world, Comar will investigate the role that Indian women played during apartheid, and in Malaysia, a country where human trafficking is still common, she will work with nongovernmental organizations that assist trafficked women in order to tell their stories. Finally, in Buenos Aires, she plans to join a studio teaching Bharatanatyam. "They're working in a foreign culture where it had not previously been appreciated," she says. "The situation has parallels to women's efforts to break into STEM [science, technology, engineering, and mathematics] fields, especially in male-dominated societies like Argentina."

Comar will be entering an MD/PhD program on her return to the United States and plans to become a physician-scientist, eventually as a professor at a medical school.

Aaron Krupp of Needham, Massachusetts, is a mechanical engineering major. Over the next year, he will be working on low-tech projects to improve the quality of life on the most basic level at sites in India, Southeast Asia, and Nepal. In India, he plans to help manufacture durable roofing tiles out of recycled cardboard. He also will be working near refugee camps along the Thai-Myanmar border to help develop charcoal-based drinking-water filtration systems, and in Nepal, he will be assembling used bicycle parts into lever-driven, variable-torque all-terrain wheelchairs.

"I am getting involved in small components of projects that are already underway," says Krupp, who currently has no post-Watson plans. For example, the water filters are the product of a lab at North Carolina State University in Raleigh, where Krupp worked last summer, and the off-roading wheelchairs are an MIT project that he first encountered in 2013 while working at a hospital in rural Haiti after the magnitude-7.0 earthquake.

The American Academy of Arts and Sciences has elected five Caltech community members as academy fellows. They are faculty members Michael B. Elowitz, professor of biology and bioengineering and an investigator with the Howard Hughes Medical Institute; Mory Gharib (PhD '83), Hans W. Liepmann Professor of Aeronautics and Bioinspired Engineering, director of the Ronald and Maxine Linde Institute of Economic and Management Sciences, and vice provost; and Linda C. Hsieh-Wilson, professor of chemistry; and Caltech trustees James Rothenberg and Maria Hummer-Tuttle. The American Academy is one of the nation's oldest honorary societies. Members are accomplished scholars and leaders representing diverse fields including academia, business, public affairs, the humanities, and the arts.

Michael B. Elowitz was noted for his work that "helped to initiate synthetic biology." Elowitz studies genetic circuits—interacting genes and proteins that enable cells to sense environmental conditions and to communicate. He and his group build simplified synthetic genetic circuits and study their effects in bacteria, yeast, and mammalian cells. He has received numerous honors in recognition of his work, including a MacArthur Fellowship in 2007.

Mory Gharib and his group use nature's own design principles—apparent in fins, wings, blood vessels, and more—as inspiration for a myriad of inventions. They have studied fluid flows inside the zebrafish heart to develop efficient micropumps and more efficient artificial heart valves, and cactus spine to develop arrays of nanoneedles, based on carbon nanotubes, for painless drug delivery. Gharib holds nearly 100 patents, and was elected to the National Academy of Engineering in 2015.

Linda C. Hsieh-Wilson was noted for her pioneering work in the new fields of chemical glycobiology and chemical neurobiology. Her work combines organic chemistry and neurobiology in order to understand how carbohydrates contribute to fundamental brain processes such as cell growth and neuronal communication, neural development, and memory at the molecular level. She and her group discovered a means for suppressing tumor-cell growth by blocking the attachment of certain sugars to proteins, restricting delivery of certain carbohydrates to proteins within the tumor.

Maria Hummer-Tuttle, a lawyer, was a partner and chair of the management committee and co–managing partner of Manatt, Phelps and Phillips in Los Angeles. She currently serves on the boards of Caltech, the J. Paul Getty Trust, the W. M. Keck Foundation, the Suu Foundation, and the Foundation for Art and Preservation in Embassies. Hummer-Tuttle is president of the Hummer Tuttle Foundation, serves on the advisory board of the USC Center on Public Diplomacy at the Annenberg School as well as on the program advisory committee of the Annenberg Retreat at Sunnylands, and is a member of the Pacific Council on International Policy, the Council on Foreign Relations, and the Getty Conservation Institute Council.

Jim Rothenberg is chairman of the Capital Group Companies, Inc. In addition to his service on the Caltech board, he serves on the boards of Capital Research and Management Company, the Capital Group Companies, Inc., and American Funds Distributors, Inc. In addition, he is a portfolio counselor for the Growth Fund of America, as well as vice chairman of the Growth Fund of America and Fundamental Investors. A chartered financial analyst, he was named to the Harvard Corporation as the treasurer of Harvard University in 2004. He also serves as a director of Huntington Memorial Hospital in Pasadena.

Elowitz, Gharib, and Hsieh-Wilson join 83 current Caltech faculty as members of the American Academy. Also included in this year's list are five alumni: Robert Cohen (MS '70, PhD '72), St. Laurent Professor of Chemical Engineering at MIT and codirector of the DuPont-MIT Alliance; Alexei Filippenko (PhD '84), professor of astronomy at UC Berkeley; Katherine Hayles (MS '69), professor of literature at Duke University; Michael Snyder (PhD'83), professor and chair of genetics at Stanford University; and Donald Truhlar (PhD '70), professor of chemistry at the University of Minnesota.

Founded in 1780 by John Adams, James Bowdoin, John Hancock, and other scholar-patriots, the academy aims to serve the nation by cultivating "every art and science which may tend to advance the interest, honor, dignity, and happiness of a free, independent, and virtuous people." The academy has elected as fellows and foreign honorary members "leading thinkers and doers" from each generation, including George Washington and Ben Franklin in the 18th century, Daniel Webster and Ralph Waldo Emerson in the 19th, and Albert Einstein and Woodrow Wilson in the 20th.

The ground beneath our feet may seem unexceptional, but it has a profound impact on the mechanics of landslides, earthquakes, and even Mars rovers. That is why civil and mechanical engineer Jose Andrade studies soils as well as other granular materials. Andrade creates computational models that capture the behavior of these materials—simulating a landslide or the interaction of a rover wheel and Martian soil, for instance. Though modeling a few grains of sand may be simple, predicting their action as a bulk material is very complex. "This dichotomy…leads to some really cool work," says Andrade. "The challenge is to capture the essence of the physics without the complexity of applying it to each grain in order to devise models that work at the landslide level."

Geobiologist Victoria Orphan looks deep into the ocean to learn how microbes influence carbon, nitrogen, and sulfur cycling. For more than 20 years, her lab has been studying methane-breathing marine microorganisms that inhabit rocky mounds on the ocean floor. "Methane is a much more powerful greenhouse gas than carbon dioxide, so tracing its flow through the environment is really a priority for climate models and for understanding the carbon cycle," says Orphan. Her team recently discovered a significantly wider habitat for these microbes than was previously known. The microbes, she thinks, could be preventing large volumes of the potent greenhouse gas from entering the oceans and reaching the atmosphere.

Credit: NASA/JPL-Caltech

Researchers know that aerosols—tiny particles in the atmosphere—scatter and absorb incoming sunlight, affecting the formation and properties of clouds. But it is not well understood how these effects might influence climate change. Enter chemical engineer John Seinfeld. His team conducted a global survey of the impact of changing aerosol levels on low-level marine clouds—clouds with the largest impact on the amount of incoming sunlight Earth reflects back into space—and found that varying aerosol levels altered both the quantity of atmospheric clouds and the clouds' internal properties. These results offer climatologists "unique guidance on how warm cloud processes should be incorporated in climate models with changing aerosol levels," Seinfeld says.

Credit: Yan Hu/Aroian Lab/UC San Diego

Tiny parasitic worms infect nearly half a billion people worldwide, causing gastrointestinal issues, cognitive impairment, and other health problems. Biologist Paul Sternberg is on the case. His lab recently analyzed the entire 313-million-nucleotide genome of the hookworm Ancylostoma ceylanicum to determine which genes turn on when the worm infects its host. A new family of proteins unique to parasitic worms and related to the early infection process was identified; the discovery could lead to new treatments targeting those genes. "A parasitic infection is a balance between the parasites trying to suppress the immune system and the host trying to attack the parasite," Sternberg observes, "and by analyzing the genome, we can uncover clues that might help us alter that balance in favor of the host."

Credit: K.Batygin/Caltech

Earth is special, not least because our solar system has a unique (as far as we know) orbital architecture: its rocky planets have relatively low masses compared to those around other sun-like stars. Planetary scientist Konstantin Batygin has an explanation. Using computer simulations to describe the solar system's early evolution, he and his colleagues showed that Jupiter's primordial wandering initiated a collisional cascade that ultimately destroyed the first generation population of more massive planets once residing in Earth's current orbital neighborhood. This process wiped the inner solar system's slate clean and set the stage for the formation of the planets that exist today. "Ultimately, what this means," says Batygin, "is that planets truly like Earth are intrinsically not very common."

Credit: Nicolás Wey-Gόmez/Caltech

Human understanding of the world has evolved over centuries, anchored to scientific and technological advancements and our ability to map uncharted territories. Historian Nicolás Wey-Gόmez traces this evolution and how the age of discovery helped shape culture and politics in the modern era. Using primary sources such as letters and diaries, he examines the assumptions behind Europe's encounter with the Americas, focusing on early portrayals of native peoples by Europeans. "The science and technology that early modern Europeans recovered from antiquity by way of the Arab world enabled them to imagine lands far beyond their own," says Wey-Gómez. "This knowledge provided them with an essential framework to begin to comprehend the peoples they encountered around the globe."

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At Caltech, researchers study the Earth from many angles—from investigating its origins and evolution to exploring its geology and inner workings to examining its biological systems. Taken together, their findings enable a more nuanced understanding of our planet in all its complexity, helping to ensure that it—and we—endure. This slideshow highlights just a few of the Earth-centered projects happening right now at Caltech.

Mohamad Abedi, a PhD candidate in bioengineering, has received a Paul & Daisy Soros Fellowship for New Americans. Thirty fellows were selected from nearly 1,200 applicants "for their potential to make significant contributions to US society, culture, or their academic field," according to the fellowship program description. Each Soros Fellow will receive up to $90,000 to help cover two years of tuition, and other educational and living expenses, while studying any subject at any university in the United States. The fellowship was established to assist young new Americans—permanent residents, naturalized citizens, or children of naturalized citizen parents—at critical points in their educations.

"I'm honored and excited to receive this fellowship. Coming to the United States provided me with a plethora of opportunities and support that allowed me to pursue my dream and be here at Caltech today," Abedi says.

Abedi was born to Palestinian refugees in the United Arab Emirates. As a child he frequently visited family in the Beddawi refugee camp in Lebanon. The lack of adequate health care resources he saw there motivated him to pursue a degree in bioengineering.

"As a bioengineer, I hope to develop low-cost medical technologies that could provide people with health care regardless of their geographical location and financial capabilities," Abedi says.

After moving with his family to California during his final year of high school, Abedi began a degree in biomedical engineering at UC Irvine, where he worked on building affordable diagnostic devices that could run on air instead of electricity. At UC Irvine, he also ventured into synthetic biology to study bacterial genetic circuits—interacting genes and proteins that enable cells to sense and communicate with one another.

Now a first-year graduate student in the lab of Mikhail Shapiro, assistant professor of chemical engineering, Abedi aims to develop tools for the noninvasive modulation of brain circuitry. These would eventually allow scientists to understand and treat neurological and psychiatric diseases involving the dysfunction of local neural circuits, such as depression or obsessive-compulsive disorder.

"Understanding the human brain, where trillions of cells work in harmony to form a magnificent structure, is arguably the most ambitious target of scientific inquiry," Abedi says. "I am interested in utilizing tools from cellular and molecular engineering to study the brain, with the overarching goal of improving human health and welfare worldwide."

Yuki Oka, an assistant professor of biology, has been named a 2015 Searle Scholar. The Searle Scholars Program provides grants to young faculty to support research in the biomedical sciences and chemistry. Fifteen scholars are named annually, each receiving $100,000 per year for three years.

"I'm very excited and honored by this award," says Oka, who studies how the brain compiles both internal and external sensory information in order to maintain homeostasis, or internal stability of the body. In particular, Oka's group studies how the brain controls the feeling of thirst, and how that feeling drives us to drink water. There are multiple processes involved in regulating thirst in the brain.

"Our research group aims to understand how these thirst signals are processed in the brain and how they ultimately drive specific behavioral outputs," Oka says. "We recently identified two distinct neural populations controlling drinking behavior in two opposite directions: driving and suppressing thirst." By manipulating these neural populations in animals, the group found that it could artificially create or suppress the desire to drink water.

Before joining the faculty at Caltech, Oka was a postdoctoral scholar at Columbia University. He received his PhD from the University of Tokyo. He is the 18th current Caltech faculty member to be named a Searle Scholar.

Although serotonin is well known as a brain neurotransmitter, it is estimated that 90 percent of the body's serotonin is made in the digestive tract. In fact, altered levels of this peripheral serotonin have been linked to diseases such as irritable bowel syndrome, cardiovascular disease, and osteoporosis. New research at Caltech, published in the April 9 issue of the journal Cell, shows that certain bacteria in the gut are important for the production of peripheral serotonin.

"More and more studies are showing that mice or other model organisms with changes in their gut microbes exhibit altered behaviors," explains Elaine Hsiao, research assistant professor of biology and biological engineering and senior author of the study. "We are interested in how microbes communicate with the nervous system. To start, we explored the idea that normal gut microbes could influence levels of neurotransmitters in their hosts."

Peripheral serotonin is produced in the digestive tract by enterochromaffin (EC) cells and also by particular types of immune cells and neurons. Hsiao and her colleagues first wanted to know if gut microbes have any effect on serotonin production in the gut and, if so, in which types of cells. They began by measuring peripheral serotonin levels in mice with normal populations of gut bacteria and also in germ-free mice that lack these resident microbes.

The researchers found that the EC cells from germ-free mice produced approximately 60 percent less serotonin than did their peers with conventional bacterial colonies. When these germ-free mice were recolonized with normal gut microbes, the serotonin levels went back up—showing that the deficit in serotonin can be reversed.

"EC cells are rich sources of serotonin in the gut. What we saw in this experiment is that they appear to depend on microbes to make serotonin—or at least a large portion of it," says Jessica Yano, first author on the paper and a research technician working with Hsiao.

The researchers next wanted to find out whether specific species of bacteria, out of the diverse pool of microbes that inhabit the gut, are interacting with EC cells to make serotonin.

After testing several different single species and groups of known gut microbes, Yano, Hsiao, and colleagues observed that one condition—the presence of a group of approximately 20 species of spore-forming bacteria—elevated serotonin levels in germ-free mice. The mice treated with this group also showed an increase in gastrointestinal motility compared to their germ-free counterparts, and changes in the activation of blood platelets, which are known to use serotonin to promote clotting.

Wanting to home in on mechanisms that could be involved in this interesting collaboration between microbe and host, the researchers began looking for molecules that might be key. They identified several particular metabolites—products of the microbes' metabolism—that were regulated by spore-forming bacteria and that elevated serotonin from EC cells in culture. Furthermore, increasing these metabolites in germ-free mice increased their serotonin levels.

Previous work in the field indicated that some bacteria can make serotonin all by themselves. However, this new study suggests that much of the body's serotonin relies on particular bacteria that interact with the host to produce serotonin, says Yano. "Our work demonstrates that microbes normally present in the gut stimulate host intestinal cells to produce serotonin," she explains.

"While the connections between the microbiome and the immune and metabolic systems are well appreciated, research into the role gut microbes play in shaping the nervous system is an exciting frontier in the biological sciences," says Sarkis K. Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and a coauthor on the study. "This work elegantly extends previous seminal research from Caltech in this emerging field".

Additional coauthor Rustem Ismagilov, the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering, adds, "This work illustrates both the richness of chemical interactions between the hosts and their microbial communities, and Dr. Hsiao's scientific breadth and acumen in leading this work."

Serotonin is important for many aspects of human health, but Hsiao cautions that much more research is needed before any of these findings can be translated to the clinic.

"We identified a group of bacteria that, aside from increasing serotonin, likely has other effects yet to be explored," she says. "Also, there are conditions where an excess of peripheral serotonin appears to be detrimental."

Although this study was limited to serotonin in the gut, Hsiao and her team are now investigating how this mechanism might also be important for the developing brain. "Serotonin is an important neurotransmitter and hormone that is involved in a variety of biological processes. The finding that gut microbes modulate serotonin levels raises the interesting prospect of using them to drive changes in biology," says Hsiao.

This work was funded by an NIH Director's Early Independence Award and a Caltech Center for Environmental Microbial Interactions Award, both to Hsiao. The study was also supported by NSF, NIDDK, and NIMH grants to Mazmanian, NSF EFRI and NHGRI grants to Ismagilov, and grants from the NIAID and Food Allergy Research and Education and University of Chicago Digestive Diseases Center Core to Nagler.